Neanderthal axial and appendicular remains from Moula-Guercy, Ardèche, France.

Excavations carried out during the 1990s at Moula-Guercy cave Ardèche, France, yielded 108 hominid specimens dating to 100-120 Ka. In this paper, we describe and compare the 39 axial and appendicular specimens not including hand and foot bones. Among these remains are a large adult femur, several clavicles, a likely antimeric pair of radial heads, and a nearly complete superior pubic ramus. Analyses of this material indicate a clear affinity with Neanderthals by the presence of large and robust muscle attachments, thick long bone cortices, a long pubic ramus, and a superoinferiorly flattened clavicle shaft. The recovered remains reveal the presence of a mature male, a smaller mature individual, possibly a reproductive age female, an immature individual of age 10-12, and a second immature individual of age 4. Future analyses on the Moula-Guercy remains will illuminate ties to other known Neanderthal populations and contribute to the ongoing debate over the relative rate of Neanderthal metric growth.

In vitro antibacterial activity of the ceftazidime-avibactam (NXL104) combination against Pseudomonas aeruginosa clinical isolates.

The ß-lactamase inhibitor avibactam (NXL104) displays potent inhibition of both class A and C enzymes. The in vitro antibacterial activity of the combination ceftazidime-avibactam was evaluated against a clinical panel of Pseudomonas aeruginosa isolates. Avibactam offered efficient protection from hydrolysis since 94% of isolates were susceptible to ceftazidime when combined with 4 µg/ml avibactam, compared with 65% susceptible to ceftazidime alone. Ceftazidime-avibactam also demonstrated better antipseudomonal activity than imipenem (82% susceptibility), a common reference treatment.

Mechanistic studies of the inactivation of TEM-1 and P99 by NXL104, a novel non-beta-lactam beta-lactamase inhibitor.

NXL104 is a potent inhibitor of class A and C serine ß-lactamases, including KPC carbapenemases. Native and NXL104-inhibited TEM-1 and P99 ß-lactamases analyzed by liquid chromatography-electrospray ionization-time of flight mass spectrometry revealed that the inactivated enzymes formed a covalent adduct with NXL104. The principal inhibitory characteristics of NXL104 against TEM-1 and P99 ß-lactamases were determined, including partition ratios, dissociation constants (K), rate constants for deactivation (k(2)), and reactivation rates. NXL104 is a potent inhibitor of TEM-1 and P99, characterized by high carbamylation efficiencies (k(2)/K of 3.7 × 10(5) M(-1) s(-1) for TEM-1 and 1 × 10(4) M(-1) s(-1) for P99) and slow decarbamylation. Complete loss of ß-lactamase activity was obtained at a 1/1 enzyme/NXL104 ratio, with a k(3) value (rate constant for formation of product and free enzyme) close to zero for TEM-1 and P99. Fifty percent inhibitory concentrations (IC(50)s) were evaluated on selected ß-lactamases, and NXL104 was shown to be a very potent inhibitor of class A and C ß-lactamases. IC(50)s obtained with NXL104 (from 3 nM to 170 nM) were globally comparable on the ß-lactamases CTX-M-15 and SHV-4 with those obtained with the comparators (clavulanate, tazobactam, and sulbactam) but were far lower on TEM-1, KPC-2, P99, and AmpC than those of the comparators. In-depth studies on TEM-1 and P99 demonstrated that NXL104 had a comparable or better affinity and inactivation rate than clavulanate and tazobactam and in all cases an improved stability of the covalent enzyme/inhibitor complex.

In vitro activity of the {beta}-lactamase inhibitor NXL104 against KPC-2 carbapenemase and Enterobacteriaceae expressing KPC carbapenemases.

BACKGROUND: NXL104 is a novel-structure beta-lactamase inhibitor with potent activity against both class A and class C enzymes. Among the class A carbapenemases, KPC-type enzymes are now spreading rapidly and KPC-related carbapenemase resistance is an emerging phenomenon of great clinical importance. The activity of NXL104 against KPC beta-lactamases was examined. METHODS: Enzymatic activity of purified recombinant KPC-2 was measured with nitrocefin as reporter substrate and inhibition by NXL104 was measured by determination of IC(50) values. Antimicrobial susceptibility testing of various beta-lactams combined with a fixed concentration of NXL104 at 4 mg/L against strains producing KPC enzymes was performed by the broth microdilution method. RESULTS: NXL104 was a potent inhibitor of KPC-2 with an IC(50) of 38 nM. NXL104 restored the antimicrobial activity of ceftazidime, ceftriaxone, imipenem and piperacillin against Enterobacteriaceae strains producing KPC-2 or KPC-3. MIC values of ceftazidime against KPC producers were reduced by up to 1000-fold by combination with NXL104. CONCLUSIONS: NXL104 inhibitory activity is unique in terms of spectrum, encompassing class A extended-spectrum beta-lactamases, class C enzymes and class A carbapenemases. Given the limited therapeutic options available for infections caused by multiresistant Enterobacteriaceae isolates, NXL104 beta-lactamase inhibitor is a promising agent to be used in combination with a beta-lactam to protect its antibacterial activity.

Mechanism of action of the antibiotic NXL101, a novel nonfluoroquinolone inhibitor of bacterial type II topoisomerases.

NXL101 is one of a new class of quinoline antibacterial DNA gyrase and topoisomerase IV inhibitors showing potent activity against gram-positive bacteria, including methicillin- and fluoroquinolone-resistant strains. NXL101 inhibited topoisomerase IV more effectively than gyrase from Escherichia coli, whereas the converse is true of enzymes from Staphylococcus aureus. This apparent target preference is opposite to that which is associated with most fluoroquinolone antibiotics. In vitro isolation of S. aureus mutants resistant to NXL101 followed by cloning and sequencing of the genes encoding gyrase and topoisomerase IV led to the identification of several different point mutations within, or close to, the quinolone resistance-determining region (QRDR) of GyrA. However, the mutations were not those that are most frequently associated with decreased sensitivity to quinolones. A fluoroquinolone-resistant mutant variant of gyrase generated in vitro was highly resistant to inhibition by the fluoroquinolones ciprofloxacin and moxifloxacin but remained fully susceptible to inhibition by NXL101. Two mutant gyrases constructed in vitro, with mutations in gyrA engineered according to those most frequently found in S. aureus strains resistant to NXL101, were insensitive to inhibition by NXL101 and had a diminished sensitivity to ciprofloxacin and moxifloxacin. Certain combinations of mutations giving rise to NXL101 resistance and those giving rise to fluoroquinolone resistance may be mutually exclusive.

Novel target sites in bacteria for overcoming antibiotic resistance.

Resistance to marketed antibiotics continues to increase. During the last 10 years some 200 bacterial genome sequences have become available, giving rise to expectations that genomics would provide a plethora of novel targets and hence a flood of new therapeutic agents. Contrary to some predictions the genomic effort has yet to yield a substantial number of novel class agents in clinical development. What are the reasons for the differences between expectations and reality? This article reviews what has been achieved in the exploitation of bacterial genomes for the discovery of novel antibacterials.

The ß-lactamase inhibitor avibactam (NXL104) does not induce ampC ß-lactamase in Enterobacter cloacae.

Induction of ampC ß-lactamase expression can often compromise antibiotic treatment and is triggered by several ß-lactams (such as cefoxitin and imipenem) and by the ß-lactamase inhibitor clavulanic acid. The novel ß-lactamase inhibitor avibactam (NXL104) is a potent inhibitor of both class A and class C enzymes. The potential of avibactam for induction of ampC expression in Enterobacter cloacae was investigated by ampC messenger ribonucleic acid quantitation. Cefoxitin and clavulanic acid were confirmed as ampC inducers, whereas avibactam was found to exert no effect on ampC expression. Thus, avibactam is unlikely to diminish the activity of any partner ß-lactam antibiotic against AmpC-producing organisms.

New inhibitors of bacterial topoisomerase GyrA/ParC subunits.

Inhibitors of the GyrA and ParC subunits of the bacterial type IIA topoisomerases DNA gyrase and topoisomerase IV, respectively, belong to classes of antibiotics that are among the most successful of the past 50 years, both in a therapeutic and a commercial sense. The initial promise of progressive modification of an antibiotic scaffold to extend the antibacterial spectrum and to modulate pharmacokinetic/pharmacodynamic parameters of existing antibiotics in an advantageous manner has been tempered by the frequent concomitant appearance of serious toxicity. The merits of the most prominent novel antibiotics that have reached, or are expected to reach the clinical phase of drug development are summarized in this review.

Taphonomic, avian, and small-vertebrate indicators of Ardipithecus ramidus habitat.

Thousands of vertebrate specimens were systematically collected from the stratigraphic interval containing Ardipithecus ramidus. The carcasses of larger mammals were heavily ravaged by carnivores. Nearly 10,000 small-mammal remains appear to be derived primarily from decomposed owl pellets. The rich avifauna includes at least 29 species, mostly nonaquatic forms. Modern analogs of the most abundant birds and of a variety of rodents are associated with mesic woodland environments distant from large water bodies. These findings support inferences from associated geological, isotopic, invertebrate, and large-vertebrate assemblages. The combined results suggest that Ar. ramidus occupied a wooded Pliocene habitat.

Morphological variation and airflow dynamics in the human nose.

Airflow dynamics are recognized as being important to the functioning of the human nose in conditioning and filtering inspired air, yet these dynamics are poorly understood. Despite considerable research on airflow dynamics by otolaryngologists, respiratory physiologists, and toxicologists, major disagreements remain about the nature of airflow in the human nose. Specifically, there is little consensus about the character of nasal airflow regimes (laminar or turbulent) and about the major pathways of airflow through the internal chamber. Additionally, a number of features in the human nose have been argued to enhance airflow turbulence, thus increasing the exposure of moving air to the nasal mucosa and facilitating heat and moisture exchange in cold and/or dry climates. These features include: an inferior orientation of the nares; a nasal sill that is high relative to the floor of the internal nasal chamber; a nasal valve that is small in cross-sectional area relative to that of the internal chamber; and large, projecting conchae. The claim that these features affect airflow dynamics has never been tested. To clarify the nature of human nasal airflow and to test these claims of functional significance to nasal variation, we studied airflow across physiological flow rates using water and dye flowing through anatomically accurate acrylic models of human nasal air passageways (with adjustment of water flow rates to maintain dynamic similarity). The models were derived from direct casting of the nasal passageways of 10 Caucasian ("leptorrhine") cadavers (six male, four female). Measures of naris angle, nasal sill height, nasal valve area relative to internal chamber cross-sectional area, and relative projection of the inferior and middle turbinates were taken directly on the resulting casts. The relationships between aspects of nasal morphology and turbulent air flow were evaluated by examining the flow regimes (laminar, semiturbulent, or turbulent) at varying flow rates, with the expectation that the greater the development of the proposed turbulence-enhancing features the slower the flow rate at which flow would shift from one regime to another. Flow characteristics (both flow regimes and principal pathways) were highly variable within our sample. The relative projection of the inferior turbinate was the only variable that significantly affected the flow rate at which flow became turbulent. However, more projecting turbinates appear to laminate flow rather than to induce turbulence. Nostril orientation was moderately correlated with flow dynamics (with more inferiorly directed nares producing turbulence at slower flow rates), but this correlation was not statistically significant. Relative nasal valve area and nasal sill height were unrelated to turbulence in our models.